A combination of modified vaccinia Ankara-5T4 (MVA-5T4) and low-dose cyclophosphamide, or either treatment given alone, demonstrated significant survival benefit in a small group of patients with metastatic colorectal cancer (mCRC) compared with no treatment, according to the results of a study published in JAMA Oncology.
“This randomized clinical trial identified a subset of immunotherapy-responsive patients with mCRC who demonstrated better tumor control when given cyclophosphamide or MVA-5T4,” wrote Martin Scurr, PhD, of Cardiff University, Wales, and colleagues. “Although cyclophosphamide failed to enhance MVA-5T4 immunogenicity, survival benefits with minimal adverse effects were demonstrated, and further investigation is warranted.”
According to the study, immunotherapy using checkpoint inhibitors has not been as successful in CRC as many other solid tumor types. The oncofetal antigen 5T4 is expressed in a majority of cases of mCRC and preliminary studies using MVA-5T4 in patients with metastatic disease showed that it was safe and induced serologic and T-cell responses.
In this phase I/II study, Scurr and colleagues randomly assigned 52 inoperable patients with stable disease following standard chemotherapy to either watch and wait, cyclophosphamide only, MVA-5T4 only, or a combination of MVA-5T4 and cyclophosphamide. The predefined primary endpoint was the magnitude of anti-5T4 immune responses generated at week 7.
Compared with the watch-and-wait group, there were significant increase in 5T4-specific antibody immune responses in patients assigned to MVA-5T4 (83.4 relative units; P = .02), and combination treatment (65.81 relative units; P = .002).
Treatment with cyclophosphamide depleted regulatory T cells in 24 of 27 patients that received MVA-5T4, which independently prolonged progression-free survival (PFS; 5 vs 2.5 months; P = .09).
“Thus, effective cyclophosphamide-induced Foxp3+ Treg cell depletion was associated with prolonged PFS, but statistical significance was not reached likely owing to sample size and the study not being powered to directly address this,” the researchers wrote.
Treatment with MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients. This resulted in a significantly prolonged progression-free survival (5.6 vs 2.4 months; P < .001) and overall survival (OS; 20 vs 10.3 months; P = .008).
No grade 3 or 4 adverse events occurred.
“Each treatment improved antitumor immunity through different mechanisms; cyclophosphamide was effective at depleting Foxp3+ Treg cells, resulting in increased anti-5T4 T-cell responses, which is associated with survival, and MVA-5T4 was effective at inducing cellular and humoral anti-5T4 responses, increasing PFS and OS in a subgroup analysis of patients with and without a treatment response,” the researchers wrote.
“In combination, however, cyclophosphamide did not improve anti-5T4 responses during MVA-5T4 treatment despite a modest increase in anti-5T4 antibody level,” they wrote. “This finding may reflect cyclophosphamide blocking the priming and proliferation of other important immune cell subsets required for effective vaccination (eg, tumor antigen–specific effector T cells and dendritic cells). Future studies will aim to decipher the exact effect of metronomic oral cyclophosphamide on immunologic responses and how it might impinge on other cell populations.”